Low Dose Pharmaceutical Powders for Inhalation

ABSTRACT

The invention relates to a method of delivering an agent to the pulmonary system of a compromised patient, in a single breath-activated step, comprising administering a particle mass comprising an agent from an inhaler containing less than 5 milligrams of the mass, wherein at least about 50% of the mass in the receptacle is delivered to the pulmonary system of a patient. The invention also relates to receptacles containing the particle mass and the inhaler for use therein.

RELATED APPLICATION

This application is a divisional of U.S. application Ser. No.10/867,375, filed Jun. 14, 2004, which claims the benefit of U.S.Provisional Application No. 60/478,315, filed on Jun. 13, 2003. Theentire teachings of the above application is incorporated herein byreference.

BACKGROUND OF THE INVENTION

Inhalation of aerosol powders from dry powder inhalers (DPI's) is aconvenient way of delivering drugs to patients, such as asthmatics.Current DPI's typically make use of small amounts of micronized drugblended with large amounts of carrier particles, such as a lactosecarrier, to facilitate efficient delivery of the drug to the lungs. Theefficiency and reproducibility of delivery of such blends is dependenton the patient's lung function and can be effected by parameters such asinspiratory flow rate and/or volume. Existing DPI's can be reservoirbased, such as those capable of storing and delivering large numbers ofdoses to patients, as well as receptacle based, such as those utilizingcapsules or blisters.

Patients that could benefit from drugs delivered via a DPI often timesdo have compromised or reduced lung function, which can alter, reduce,or delay the efficiency of delivery or therapeutic onset of the drug.Conditions leading to such compromised lung function include asthma,COPD, anaphylaxis, emphysema, and other forms of respiratory distress.Other factors such as a patient's age (i.e. children or elderlypatients), history (i.e. smoking, chemical exposure) and otherconditions can also lead to a reduction of inspiratory flow rate and/orvolume.

A need exists to be able to efficiently and reproducibly delivertherapeutic agents to the lungs of such compromised patients. This wouldoptimally utilize low masses of dry particles capable of being deliveredvia a single breath-activated step, especially at low inspiratory flowrates and/or low inspiratory volumes. Also, a need exists to deliver alarge fraction of the mass of such particles from the DPI to thepulmonary system of a compromised patient.

SUMMARY OF THE INVENTION

It is therefore an object of the invention to deliver an effectiveamount of therapeutic, prophylactic or diagnostic agents by dry powderaerosols without the need for particle levels typically found withcapsule-based delivery systems, such as those including a carrier.

It is therefore an object of the invention to deliver an effectiveamount of therapeutic, prophylactic or diagnostic agents by dry powderaerosols having lower dose levels, for example, less than 5 mg.

It is another object of the invention to deliver an effective amount oftherapeutic, prophylactic or diagnostic agents by dry powder aerosolshaving lower dose levels, for example, less than 5 mg to compromisedpatients having low inspiratory flow rates of less than 20 L/minute.

It is another object of the invention to deliver a dry powder aerosolwith a respirable fraction (<4.7 μm) of 45% or more which maintains ahigh emitted dose over a very broad flow rate range, such as between15-60 L/min.

The invention relates to a method of delivering an agent to thepulmonary system of a compromised patient, in a single breath-activatedstep, comprising administering a particle mass comprising an agent froman inhaler containing less than 5 milligrams of the mass, wherein atleast about 50% of the mass in the receptacle is delivered to thepulmonary system of the patient.

In another embodiment, the invention relates to a receptacle containingless than 5 milligrams of particle mass comprising an agent wherein,upon delivery to the pulmonary system of a compromised patient, in asingle breath-activated step, at least about 50% of the mass in thereceptacle is delivered to the pulmonary system of the patient.

Further, the invention relates to an inhaler for use in a method fordelivering an agent to the pulmonary system of a compromised patient, ina single breath-activated step comprising administering a particle masscomprising an agent from an inhaler containing less than 5 milligrams ofthe mass, wherein at least about 50% of the mass in the receptacle isdelivered to the pulmonary system of the patient.

BRIEF DESCRIPTION OF THE FIGURES

The present invention is described with reference to the accompanyingdrawings.

In the drawings, like reference numbers indicate identical orfunctionally similar elements.

FIG. 1 is a front view of one embodiment of a device of the presentinvention;

FIG. 2 is a cross-section of the device shown in FIG. 1 along line 2-2;

FIG. 3 is an enlarged partial cross-section of one embodiment of adispersion chamber of the present invention;

FIG. 4 is an enlarged partial cross-section of another embodiment of adispersion chamber of the present invention showing one location for aring in the dispersion chamber;

FIG. 5 is an enlarged partial cross-section of another embodiment of adispersion chamber of the present invention showing another location fora ring in the dispersion chamber;

FIG. 6 is an enlarged partial cross-section of another embodiment of adispersion chamber of the present invention showing another location fora ring in the dispersion chamber;

FIG. 7A is a top view of a preferred embodiment of a staple suitable foruse with the device of the present invention;

FIG. 7B is a front view of the embodiment shown in FIG. 7A;

FIG. 7C is a side view of the embodiment shown in FIG. 7A;

FIG. 7D is an isometric view of the embodiment shown in FIG. 7A;

FIG. 8 is a bar graph illustrating emitted dose at flow rates of 20L/min (left bar), 40 L/min (center bar), and 60 L/min (right bar) forfour dispersion chamber configurations;

FIG. 9 is a bar graph illustrating emitted dose at low flow rates fordevices with varying numbers of slits;

FIG. 10 is a bar graph illustrating the percentage emitted dose as afunction of air volume;

FIG. 11 shows radiolabeling validation data for the 5 mg placeboformulation;

FIG. 12 shows emitted dose (ED) as a function of pulmonary inspiratoryflow rate (PIFR);

FIG. 13 shows the lung deposition of the total dose as a function ofPIFR;

FIG. 14 shows AIR-epinephrine performance across inhalation flow rates;

FIG. 15 shows the emitted dose versus power for different inhalers;

FIG. 16 shows the fine particle fraction (%<3.3 microns) versus powerfor different inhalers: The Eclipse, C2S (preferred inhaler of theinstant invention), Diskhaler and Inhalator;

FIG. 17 shows the emitted dose apparatus;

FIG. 18 shows the emitted dose as a function of flowrate;

FIG. 19 shows the emitted dose as a function of inhaled volume; and

FIG. 20 shows the lung deposition as a function of inhaled volume.

DETAILED DESCRIPTION

The invention relates to a method of delivering an agent to thepulmonary system of a compromised patient, in a single breath-activatedstep, comprising administering a particle mass comprising an agent froman inhaler containing less than 5 milligrams of the mass, wherein atleast about 50% of the mass in the receptacle is delivered to thepulmonary system of the patient.

Applicants have been improving methods of delivering particle masses, inparticular, dry particles for oral delivery. Applicant have discoveredmethods to deliver an effective amount of therapeutic, prophylactic ordiagnostic agents by dry particles aerosols having lower dose levels,for example, less than 5 mg, in particular, in the range of 3 mg to 5mg. Until the present invention, it has been a challenge to administeraerosols having lower dose levels, for example, less than 5 mg tocompromised patients having low inspiratory flow rates, for example,less than 20 L/minute. Applicant have been able to deliver a chemicallystable dry particle aerosol with a respirable fraction (<4.7 μm) of 45%which maintains a high emitted dose (>80%) over a flow rate range of15-60 L/min, that is, over a range of inhalation flow rates.

Compromised patients include individuals who do not or cannot breathehard or have a compromised lung function. Examples of such individualsinclude children, including growth hormone deficient children, elderlypersons, persons suffering from respiratory disease, such as conditionsleading to such compromised lung function include asthma, COPD,anaphylaxis, emphysema, and other forms of respiratory distress. Otherfactors such as a patient's age (i.e. children or elderly patients),history (i.e. smoking, chemical exposure) and other conditions can alsolead to a reduction of inspiratory flow rate and/or volume. Otherindividuals include sleeping individuals and comatose individuals.Preferably, the individuals are vertical during the method. However, itis also possible to practice the method horizontally. Preferably, humangrowth hormone is administered to children at doses of less than 5 mg,such as less than 4 mg.

Generally, the individual will have a peak inspiratory flow rate (PIFR)of less than about 20 liters per minute. In one embodiment, the patientwill have a PIFR of about 15 liters per minute or less. Alternatively oradditionally, the compromised patient has an inspiration volume of lessthan 2 liters, such as less than 1.5 liters, including less than 1liter, such as 0.75 liters.

The method is particularly useful in delivering agents that are usefulin treating the cause of the patient's compromised state, such asadministering epinephrine for treating or preventing anaphylaxis, growthhormone for growth hormone deficient children, or asthma medications,such as albuterol, fluticasone formoterol, ipatroium bromide, trospiumchloride or salmeterol, for treating asthma.

A particular advantage of the invention rests in the discovery thatdelivery of very small amounts of drug (e.g. particle mass) can beachieved independently of PIFR. This unexpected discovery permitsreliable and reproducible dosing for the patient, irrespective of thepatient's particular condition and the need to determine the patient'sactual flow rate prior to administering the dose, even at very low dosesof particle mass.

Thus, in a preferred embodiment, the inhaler, or the receptacle whichmay be disposed within the inhaler, contains less than 4 milligrams ofthe particle mass, preferably less than about 3 milligrams (such asabout 3.4 mg). In one embodiment, the mass of particles containsepinephrine at a dose of about 250 to 750 micrograms of epinephrine.

The particle mass is highly dispersible and possesses good to excellentdeposition in the lung. Examples of preferred particle masses possess atap density of less than about 0.4 g/cm³, preferably less than about 0.1g/cm³, such as less than about 0.05 g/cm³. Tap density is a measure ofthe envelope mass density characterizing a particle. The envelope massdensity of particles of a statistically isotropic shape is defined asthe mass of the particle divided by the minimum sphere envelope volumewithin which it can be enclosed.

Preferred particle masses possess a mass mean geometric diameter of themass, as emitted from the inhaler, between about 1 micron and 20microns, such as between about 3 and 15 microns, more preferably betweenabout 3 microns and 10 microns. Good deposition to the lung can beachieved with particle masses possessing a preferred mass meanaerodynamic diameter of the mass emitted from the inhaler is betweenabout 1 to 5 microns, such as between about 1 and 3 microns. Preferredparticles masses include or consist of spray-dried particles.

Features that can contribute to low tap density, large geometricdiameter and low aerodynamic diameter include irregular surface textureand hollow or porous structure. Particularly preferred particles andparticles are described in U.S. Pat. Nos. 6,136,295, 5,985,309,5,874,064, and 5,855,913, and 6,858,199, the entirety of each of theforegoing patents is hereby incorporated herein by reference.

Other particles that can be useful in the claimed invention includethose manufactured under the trademark PULMOSPHERES, developed by NektarTherapeutics.

The method of the invention results in good to excellent emitted dosesof the particle mass. In one embodiment, the emitted dose is at least50%, preferably at least about 60%, more preferably at least about 70%.In a particularly preferred embodiment, the achieved emitted dose can begreater than about 80% such as at least about 85%.

The method can be readily achieved using an inhaler disclosed in thepatent application filed in the United States Patent & Trademark Officeon Oct. 10, 2002, having the title “Inhalation Device and Method” byEdwards et al., U.S. patent application Ser. No. 10/268,059, now U.S.Pat. No. 6,732,732, issued Oct. 11, 2004. Other inhalers that can beused include those described in PCT publication WO 02/083220, having thetitle “Inhalation Device and Method,” by Edwards et al. published onOct. 24, 2002. The contents of the applications are incorporated hereinby reference in their entirety, together with their priority documents.

Alternative inhalers which can be used in the method are dry powderinhalers, including capsule loaded inhalers. Examples of suitable drypowder inhalers include but are not limited to the inhalers disclosed inU.S. Pat. Nos. 4,995,385 and 4,069,819, SPINHALER (Fisons, UK),ROTAHALER (GlaxoSmithKline, N.C.), FLOWCAPS (Hovione, Switzerland),INHALATOR (Boehringer-Ingelhein, Germany), AEROLIZER (Novartis,Switzerland), and the ECLIPSE (Aventis) and blister-based inhalers, suchas DISKHALER (GSK, NC), and DISKUS (GSK, NC).

The selected low amounts of epinephrine particles used in the instantinvention are 3.36 mg particle for delivery of lowest dose (300 ugepinephrine) which is an extremely low powder dose for inhalation. Thecombination of the dry powder aerosol with a respirable fraction (<4.7μm) of 45% and the preferred inhaler maintained an unexpectedly highemitted dose. This translates into the ability to treat highlycompromised patients and in particular, highly compromised children.

The Applicant compared the effectiveness of the instant inventionagainst other available technologies. For example, the emitted dose datacomparing the Diskhaler, Inhalator, Eclipse and C2S inhaler, shown inFIGS. 15 and 16, and FPF (%<3.3 microns) were preformed using 5.6 mg,corresponding to 500 μg active epinephrine which was used in the humanclinical trial performed by Applicant. Inspiratory flow rates of 15, 30and 60 L/min with a total volume of 2 liters were used for all theinhalers and then plotted as power (in watts) versus emitted dose. Poweris a function of flowrate and resistance with each inhaler tested havinga different resistance.

The formula used to calculate Power is:

Power=Flowrate³×Resistance²

As indicated by the results, the comparison showed that at the low flowrate of 15 L/min in asthmatic patients in a compromised state(corresponding to less than 0.5 watts power for all inhalers tested)there is a fall off in emitted dose for all the inhalers except for theC2S inhaler, a preferred inhaler for the instant invention.

The same experiments were performed testing the lower epinephrine fillweight of 3.36 mg. This corresponds to 300 μg epinephrine at 15 L/min.The emitted dose was measured and the data shown in FIG. 14,demonstrating that less than about 5 mg particle mass were developed atless than about 20 L/min. More particularly, as shown, the emitted dosedata for a 3.36 mg filled capsule is shown in FIG. 14. This comparesfavorably to the previous emitted dose data generated for the 5.6 mgfill weights.

Applicant employed two methods to obtain a measure of the emitted dose.A gravimetric analysis and a chemical analysis. Applicant performed theanalysis according to the standard operating procedure (SOP) describedbelow.

Applicant tested the particles under controlled environmental conditionsof a room temperature of greater than about 18° C. but less than about25° C. and a relative humidity of between about 20 and about 40. Theequipment used in the Examples is shown in FIG. 17.

In performing the tests, a filled capsule was placed in the inhaler.Holding the inhaler vertically with the mouthpiece up, the capsule waspunctured. The inhaler was placed in the inlet of the apparatus shown inFIG. 17, ensuring an airtight seal. Next the pump was activated usingthe flow controller. The flow rate selected was either 60 (±2) L/min for2 seconds or a flow rate of 30 (±2) L/min for 4 seconds or a flow rateof 15 L/min for 8 seconds. In order to ensure that an airtight seal wasattained, an equal flow rate was maintained in both meters (±2 L/min).

After performing the experiments and collecting the data, using thefollowing formulae, the emitted dose was calculated.

${ED} = {\frac{\left( {m_{f\; 1} - m_{f\; 0}} \right)}{m_{fw}} \times 100}$

Where ED [%] is the emitted dose of the particles and m_(f0) [mg] is themass of the filter, m_(f1) [mg] is the mass of the particle-laden filterand m_(fw) [mg] is the actual or nominal fill weight.

Experiments in humans were conducted to evaluate the in vivo dosedelivery characteristics of the delivery system of the instant inventionover a wide range of inspiratory flow rates. The in vivo dose deliveryof the pulmonary delivery system of the instant invention wascharacterized at a target peak inspiratory flow rate (PIFR) of 60 L/min(Dunbar et al., Int. J. Pharm. 245, 2002).

Twelve healthy volunteers participated in a single center, randomized,three period, cross-over study. Each volunteer performed the followingthree inhalation maneuvers: (i) a targeted peak inspiratory flow rate(PIFR) of 20 L/min, (ii) a deep comfortable inhalation, and (iii) a deepforced inhalation. Volunteers inhaled the radiolabeled placebo particlessitting upright, with their head and lungs posterial to the planar gammacamera. After a 5 s breath hold, the volunteers were instructed toexhale into a filter. Peak inspiratory flow rate (PIFR) and inhaledvolume (V) were obtained during the inhalation of the dose using aspirometer (Koko Spirometer, Pulmonary Data Services Inc., Louisville,Colo.). Immediately following the radiolabeled dose, posteriorscintigraphic images were taken using a planar gamma camera (DIACAM,Siemens Gammsonics, Inc., Hoffman Estates, Ill.). Four regions ofinterest were drawn around the left lung, right lung, stomach, andoropharynx (which included the upper part of the trachea). Aftersubtracting the background activity, each region was corrected fortissue attenuation. The radioactivity in the pre-dosed capsule and theradioactivity remaining in the inhaler mouthpiece, inhaler body,post-dosed capsule, and exhalation filter were measured by scintigraphyusing a high sensitivity NaI detector (Model 905, Perkin-Elmer, OakRidge, Tenn.). PIFR, emitted dose (ED), and lung deposition of the totaldose were evaluated in this study.

The mean ED and lung deposition across all three inhalation maneuverswere 87 (4) % and 51 (10) %, respectively (sd in parentheses). The rangeof PIFRs obtained in this study was 12-86 L/min. The emitted dose andthe lung deposition of the total dose as a function of PIFR are shown inthe figures.

In conducting the human scintigraphy, 5 mg placebo was delivered via asimple, capsule based, passive dry powder inhaler such as the preferredinhaler described herein. The particles was radiolabeled with 99 mTcusing a fluidized bed process (Dunbar et al., Int. J. Pharm., 245,2002). Validation experiments were conducted to ensure the radiolabelingprocess did not significantly affect the aerodynamic particle sizedistribution (aPSD) of the emitted dose and the radioactive aPSD matchedthe mass aPSD. The mass aPSD of the unlabeled particles, the mass aPSDof the labeled particles, and the radioactive aPSD of the labeledparticles were obtained using an 8-stage Andersen cascade impactor(Andersen Instruments, Smyrna, Ga.) with a USP induction port, shown inFIG. 11.

In a preferred embodiment, the inhaler comprises: a first casingportion; a cylindrical chamber, defined by a wall of circularcross-section, coupled to the first casing portion, the chamber having aproximal end and a distal end, the chamber comprising a ringcircumferentially coupled to an inner surface of the chamber; and asecond casing portion removably coupled to the first casing portion, thesecond casing portion comprising an inhalation portion disposed at theproximal end of the chamber when the first and the second casingportions are coupled, the inhalation portion comprising a hemisphericregion defining a plurality of apertures configured to emit the mass.

As will be described in more detail below, an apparatus of the presentinvention is an inhaler that includes a chamber. In one embodiment, thechamber is configured to receive the receptacle containing themedicament. To improve the emptying of the receptacle and provide ahigher reproducible emitted dose, the chamber includes a ringcircumferentially coupled to an inner surface of the chamber. The ringis preferably disposed at approximately a midpoint of the chamber, oralternatively, adjacent the proximal end of the chamber. In proper use,air will exit the inhaler carrying a full dose of medicament in the formof a fine, dry particle mass.

The inhaler of the present invention is preferably configured with ameans for puncturing the receptacle that improves puncturingperformance, particularly with brittle receptacle material. The meansfor puncturing the receptacle of the present invention is preferablyconfigured as a substantially U-shaped staple with two prongs, eachprong having a sharp point and two cutting edges. In one embodiment ofthe present invention, each prong has a square cross-section, with thestaple material being bent around a face so that the innermost part ofthe U-shaped staple is flat. In another embodiment of the presentinvention, the staple material is rotated 45 degrees so that it is bentaround an edge so that the innermost part of the U-shaped staple is anedge. In such an embodiment, the end surface of each prong is an angleddiamond-shaped surface.

The methods of the present invention use an inhaler to dispense particleby inhalation. As will be discussed in greater detail below, a useroperates the device to puncture the receptacle to disperse particles inthe chamber, and inhales the particles through the inhalation portion.

A front view of one embodiment of an inhalation device 100 of thepresent invention is shown in FIG. 1. The rear view of device 100 issubstantially identical to the front view. Device 100 includes a firstor lower casing portion 120 and a second or upper casing portion 130removably coupled to first casing portion 120. Upper casing portion 130and lower casing portion 120 include a flattened region 132 and 122,respectively, for ease of gripping the casing for use by a patient.Lower casing portion 120 preferably includes an outer casing 126 and aninner casing 124 movably received within outer casing 126. A removablecap 110 is provided at the user or inhalation end of the device.Preferred materials for device 100 include Food and Drug Administration(FDA) approved, USP tested plastics. Preferably, device 100 ismanufactured using an injection molding process, the details of whichwould be readily apparent to one skilled in the art. FIG. 2 is across-section of device 100 shown in FIG. 1 along line 2-2. As shown inFIG. 2, device 100 includes an inhalation or emitter portion 220Inhalation portion 220 comprises a hemispheric region 222 that defines aplurality of apertures 224. It should be understood that the presentinvention is not limited to a particular number of apertures 224, andcan be configured such that at least one aperture 224 is provided. Aninhalation piece 226 is provided to allow for inhalation of themedicament by a user.

Inhalation piece 226 can be configured as a mouth piece for inhalationthrough a user's mouth. Alternatively, inhalation piece 226 can beconfigured as a nose piece for inhalation through a user's nose.

Device 100 includes a cylindrical chamber 210 that is defined by astraight wall 212 of circular cross-section. Chamber 210 has a proximalend 214 and a distal end 216. A plurality of slits 218 are defined bywall 212, and are configured for introducing air into chamber 210 todisperse particles released from a capsule 219. It should be understoodthat the present invention is not limited to a particular number ofslits 218, and can be configured such that at least one slit 218 isprovided. Particles released from capsule 219 is dispersed in chamber210 and inhaled through apertures 224 and inhalation piece 226 by theuser.

In other embodiments of the invention, receptacles other than capsulesare used, such as blisters and film covered container wells as is knownin the art. In one embodiment, the volume of the receptacle is at leastabout 0.37 cm³. In another embodiment, the volume of the receptacle isat least about 0.48 cm³. In yet another embodiment, the receptacles havea volume of at least about 0.67 cm³ or 0.95 cm³. In one embodiment ofthe invention, the receptacle is a capsule designated with a capsulesize 2, 1, 0, 00, or 000. Suitable capsules can be obtained, forexample, from Shionogi (Rockville, Md.). Blisters can be obtained, forexample, from Hueck Foils, (Wall, N.J.).

The receptacle encloses or stores particles, also referred to herein aspowders. The receptacle is filled with particles in a manner known toone skilled in the art. For example, vacuum filling or tampingtechnologies may be used. Generally, filling the receptacle with powdercan be carried out by methods known in the art.

Device 100 includes a means for puncturing 230 that is used to puncturecapsule 219 to release particles contained therein into chamber 210. Inthe embodiment shown in FIG. 1, means for puncturing 230 is configuredas a substantially U-shaped staple having two prongs 232. In thisembodiment, each of prongs 232 is configured with a square cross-section234, thereby providing a sharp point and two cutting edges. As discussedin more detail below, device 100 could alternatively be configured withthe puncturing implement shown in FIGS. 7A through 7D. As can be readilyappreciated by one skilled in the art, the present invention is notlimited to use of a substantially U-shaped staple as the means forpuncturing the capsule. Alternatively, one, or a plurality of, straightneedle-like implements could be used. Preferably, the puncturingimplement is configured to puncture at least two holes in the capsule.

Means for puncturing 230 is preferably configured to be movable betweena non-puncturing position (as depicted in FIG. 1) and a puncturingposition. In the puncturing position, prongs 232 pierce or puncturecapsule 219 to make holes therein. In a preferred embodiment, a meansfor biasing is provided that biases the means for puncturing 230 in thenon-puncturing position. In the embodiment shown in FIG. 2, the meansfor biasing is configured as a spring 242 that biases the substantiallyU-shaped staple in the non-puncturing position.

As noted with respect to FIG. 1, device 100 includes inner casing 124and outer casing 126. As shown in FIG. 2, a spring 244 is disposed inlower casing portion 120 that biases inner casing 124 in an outwardposition. Upon compression of spring 244, inner casing 124 moves fromthe outward position to an inward position, thereby drawing lower casingportion 120 toward upper casing portion 130. Compression of spring 244also causes compression of spring 242, thereby causing means forpuncturing 230 to move to the puncturing position. Upon release ofcompression, springs 242 and 244 return to their biased state, therebyreturning means for puncturing 230 to its non-puncturing position, andinner casing 124 to its outward position.

A pair of flanges 252 is disposed on first casing portion 120. A pair ofgrooves 254 is disposed on second casing portion 130 so that flanges 252can be received within grooves 254 to thereby couple the first andsecond casing portions. Preferably, the first and second casing portionsare coupled with a friction-fit engagement. A friction-fit engagementcan be achieved using the groove and flange arrangement depicted in FIG.2.

Other alternative configurations for a friction-fit engagement would bereadily apparent to one skilled in the art.

FIG. 3 is an enlarged partial cross-section of one embodiment of chamber210. In the embodiment shown in FIG. 3, chamber 210 does not contain aring disposed on an inner surface, and an inner diameter of chamber 210is depicted as “X”. Such a configuration may be referred to herein as a“straight” chamber configuration. FIG. 4 is an enlarged partialcross-section of another embodiment of chamber 210. In the embodimentshown in FIG. 4, a ring 400 is circumferentially coupled to an innersurface of chamber 210. An inner diameter of ring 400 is depicted as“Y”, and is less than inner diameter X of chamber 210. In the embodimentshown in FIG. 4, ring 400 is disposed at approximately a midpoint ofchamber 210. Such a configuration may be referred to herein as a “low”ring position or “low” chamber configuration. As shown in FIG. 4, in thelow ring position, ring 400 is disposed adjacent slits 218. The ringposition is measured by the distance from the top of hemispheric region222 to the bottom edge of ring 400. This distance is depicted as “Z”.The following dimensions are provided as exemplary dimensions of adevice of the present invention. It should be understood by one skilledin the art that the present invention is not limited to the dimensionsprovided herein, or to any particular dimensions. In one embodiment ofthe chamber 210 shown in FIG. 4, diameter X is 0.47 in., diameter Y is0.38 in., and distance Z is 0.49 in.

FIG. 6 is an enlarged partial cross-section of another embodiment ofchamber 210. In the embodiment shown in FIG. 6, ring 400 iscircumferentially coupled to an inner surface of chamber 210. An innerdiameter of ring 400 is depicted as “Y”, and is less than inner diameterX of chamber 210. In the embodiment shown in FIG. 6, ring 400 isdisposed adjacent the proximal end of chamber 210. Such a configurationmay be referred to herein as a “high” ring position or a “high” chamberconfiguration. The ring position is measured by the distance from thetop of hemispheric region 222 to the bottom edge of ring 400. Thisdistance is depicted as “Z”. The following dimensions are provided asexemplary dimensions of a device of the present invention. It should beunderstood by one skilled in the art that the present invention is notlimited to the dimensions provided herein, or to any particulardimensions. In one embodiment of the chamber 210 shown in FIG. 6,diameter X is 0.47 in., diameter Y is 0.38 in., and distance Z is 0.29in.

FIG. 5 is an enlarged partial cross-section of another embodiment ofchamber 210. In the embodiment shown in FIG. 5, ring 400 iscircumferentially coupled to an inner surface of chamber 210. An innerdiameter of ring 400 is depicted as “Y”, and is less than inner diameterX of chamber 210. In the embodiment shown in FIG. 5, ring 400 isdisposed between the low ring position of FIG. 4 and the high ringposition of FIG. 6.

Such a configuration may be referred to herein as a “mid” ring positionor “mid” chamber configuration. The ring position is measured by thedistance from the top of hemispheric region 222 to the bottom edge ofring 400. This distance is depicted as “Z”. The following dimensions areprovided as exemplary dimensions of a device of the present invention.It should be understood by one skilled in the art that the presentinvention is not limited to the dimensions provided herein, or to anyparticular dimensions. In one embodiment of the chamber 210 shown inFIG. 5, diameter X is 0.47 in., diameter Y is 0.38 in., and distance Zis 0.39 in.

In one embodiment of the present invention, ring 400 is integral withchamber 210. In such an embodiment, ring 400 and chamber 210 are formedas a unit, such as through an injection molding, extrusion or a castingprocess. In another embodiment of the present invention, ring 400 isattached to the inner surface of chamber 210 in a manner known to thoseskilled in the art, such as through the use of glue or other type ofadhesive, or by using an attaching device such as a pin or screw, etc.Preferably, the casing of device 100 is made from a material that can beinjection molded, such as a plastic material (preferably FDA approved,USP tested). As would be readily apparent to one skilled in the art, thematerial is preferably durable, easy to clean, and non-reactive withparticles medicaments.

FIG. 8 is a bar graph illustrating emitted dose at flow rates of 20L/min (left bar), 40 L/min (center bar), and 60 L/min (right bar) for atotal volume of 2 L for four dispersion chamber configurations (standarddeviations shown; sample size (n=3)). The flow rates were measured witha flow meter. The emitted dose measurement involved placing a capsuleinto four embodiments of the inhaler of the present invention foractuation into an emitted dose (ED) measurement apparatus. The EDapparatus included a powder filter and a filter holder. The particlescollected by the ED apparatus were quantified by fluorescencespectrophotometry. The straight configuration is shown in FIG. 3; thelow configuration is shown in FIG. 4; the mid configuration is shown inFIG. 5; and the high configuration is shown in FIG. 6. As can be seenfrom FIG. 8, each of the low, mid, and high configurations demonstrateda higher emitted dose at each of the three flow rates than the straight(no ring) configuration. Thus, the ring configuration of the presentinvention provides an improvement over conventional chamber designswithout a ring. At each of the flow rates shown in FIG. 8, the lowconfiguration produced a higher emitted dose and a lower standarddeviation than the mid and high configurations.

FIG. 9 is a bar graph illustrating emitted dose at low flow rates fordevices with varying numbers of slits 218. A flow rate of less thanabout 15 L/min will be referred to herein as a “low flow rate.” Themeasurements were taken at a flow rate of 5 L/min, with a volume of 67cc and a 15 mg dosage. As show in FIG. 9, by decreasing the number ofslits 218, the emitted dose increases so that the device of the presentinvention successfully delivers a high emitted dose at low flow rateover multiple (ten) actuations. Thus, the device of the presentinvention achieves a high emitted dose at low flow rates that isconsistently reproducible with low standard deviation.

Experiments were conducted to evaluate the emitted dose as a function ofair volume drawn through the inhaler. The inhaler was operated at aconstant flow rate of 30 L/min for a 5 mg dose. The volume of airthrough the inhaler was varied by varying the actuation time. Volumes of0.5, 1.0, 1.5, 2.0 and 3.0 L were investigated. FIG. 10 shows thepercentage emitted dose as a function of air volume (n=3, standarddeviations shown).

The emitted dose remained constant across the range of volumes and wasconsistently reproducible with low standard deviation.

In the embodiments having the inner diameter X of chamber 210 of 0.47in. and the inner diameter Y of ring 400 of 0.38 in., the ratio of theinner diameter of the ring to the inner diameter of the chamber is about0.8. By modifying the inner diameters of the ring and the chamber, it ispossible to optimize the emitted dose at varying flow rates. As reportedin Annals of the ICRP, Human respiratory tract model for radiologicalprotection, 24 (1-3), Elsevier Science, New York, 1994, the flow ratefor a tidal breathing seated adult male is 300 mL/s (18 L/min) for avolume of 750 mL. In one embodiment of a device of the present inventionoptimized for low flow rates (less than about 15 L/min), inner diameterX of chamber 210 is 0.33 in. and inner diameter Y of ring 400 is 0.30in. In such an embodiment, the ratio of the inner diameter of the ringto the inner diameter of the chamber is about 0.9. Preferably, the ratioof the inner diameter of the ring to the inner diameter of the chamberis about 0.9 or less.

The device of the present invention can also be optimized for varyingdosage ranges. One way to do so is to vary the dimensions of chamber 210to accommodate varying sizes of capsules. For example, a chamber havingan inner diameter X of 0.33 in., inner diameter Y of 0.30 in., anddistance Z of 0.57 in. can be used with size 2 and size 00 capsules. Oneskilled in the art can scale chamber 210 to accommodate varying capsulesizes, and to accommodate those capsule sizes at varying flow rates.

The present invention further encompasses optimizing the configurationof device chamber 210 in order to maintain a low resistance of 0.28 (cmH₂O)^(1/2)/L/min or less and to achieve an emitted dose of at least 50%when the receptacle contains a dose of up to 5 mg of particles and whenthe device is operated at a peak inspiratory flow rate of 20 L/min orless and/or at an inhalation volume of 0.75 L or less. Experiments wereperformed on various chamber configurations, using size 00 capsulesfiled with a 20 mg dose of standard test powder. The variousconfigurations were tested for emitted dose (ED), using known methodsdescribed above, at peak inspiratory flow rates ranging from 15 L/min to25 L/min and at inhalation volumes ranging from 0.25 L/min to 0.75L/min. In addition, the dispersion of the particles was quantified bymeasuring the volume mean geometric diameter (VMGD) of the emittedparticles, by employing a RODOS dry powder disperser (or equivalenttechnique) such that at about 1 Bar, particles of the dry powder emittedfrom the RODOS orifice with geometric diameters, as measured by a HELOSor other laser diffraction system, are less than about 1.5 times thegeometric particle size as measured at 4 Bar. In addition, theresistance of each chamber was measured using methods that will beapparent to one of ordinary skill in the art.

The following dimensions of chamber 210 were varied in order to discoverthe optimal combination: mouthpiece hole area, mouthpiece hole number,chamber diameter (X in FIG. 4), ring diameter (Y in FIG. 4), vent area(the product of vent width, vent height, and vent number), and capsulehole area (the product of the hole area and the number of holes).Initially, it was discovered that it is always desirable to maximize thecapsule hole area. Accordingly, the capsule hole area was fixed at 0.013square inches. It should be understood that the present inventionencompasses other capsule hole areas, especially when used withdifferent sized capsules. It was also determined that the total area ofthe holes in the mouthpiece was an important factor but that the numberof holes in the mouthpiece did not effect the results.

Next, 130 chambers were tested, each having a different combination ofmouthpiece hole area, chamber diameter, ring diameter, and vent area.During the testing it was discovered that each of these dimensions havecompeting effects on the emitted dose, the volume mean geometricdiameter, and the resistance of the chamber. For example, increasing thevent area has a positive impact on (i.e., decreases) resistance, but hasa negative effect on (i.e., decreases) emitted dose and has a negativeeffect on (i.e., increases) volume mean geometric diameter. Otherdimensions have similar competing effects. In addition, as discussed indetail below, the vent area and the chamber diameter have combinationaleffects on the properties of the chamber. Other combinations ofdimensions have similar combinational effects.

Of the 130 chambers tested, three preferred embodiments of chambers wereidentified that achieved the desired characteristics. The pertinentdimensions of each of those chambers is described in Table 1.

TABLE 1 Aspects of Preferred Embodiments of Chambers Chamber F Chamber HChamber I Resistance (cm H₂O)^(1/2)/L/min 0.27 0.22 0.19 Mouthpiece HoleArea (sq. in.) 0.020 0.022 0.022 Chamber Diameter (in.) 0.440 0.4360.440 Ring Diameter (in.) 0.400 0.380 0.400 Vent Area (sq. in.) 0.0140.020 0.024 Vent Number (in.) 3 4 5 Vent Width (in.) 0.020 0.025 0.020Vent Length (in.) 0.236 0.195 0.236

Tables 2-4 summarize the emitted dose (ED) (in percent) and dispersion(volume mean geometric diameter (VMGD) in microns)) (with standarddeviations in parentheses) achieved with each of these preferredembodiments of chambers, operated with a capsule having a dose ofapproximately 20 mg and at peak inspiratory flow rates from 15 L/min to25 L/min and at inhalation volumes from 0.25 L to 0.75 L. The testparticle mass, referred to herein as “standard test powder,” was aplacebo powder of 84.99 wt % maltodextran, 15 wt % leucine, and 0.01 wt% rhodamine. It had a VMGD of 12 μm measured using the RODOS at 1 barand an aerodynamic size (volume mean aerodynamic diameter or VMAD) of 3μm measured using an 8 stage Anderson Cascade Impactor. The goal emitteddose was at least 85%. The goal dispersion for the standard test powderwas a VMGD of 11.8 μm or less, although it should be understood thatthis goal would vary depending on the type of powder used.

TABLE 2 Chamber F Volume 0.25 L 0.5 L 0.75 L Flow Rate VMGD ED VMGD EDVMGD ED 15 L/min 15.0 (0.8)  67 (14) 13.5 (0.8)  87 (6) 16.4 (1.6)  93(3) 20 L/min 10.2 (0.5) 66 (9) 9.3 (0.6) 89 (4) 9.0 (0.6)  88 (10) 25L/min  9.3 (0.6) 77 (8) 7.8 (0.3) 91 (5) 7.9 (0.5) 93 (3)

TABLE 3 Chamber H Volume 0.25 L 0.5 L 0.75 L Flow Rate VMGD ED VMGD EDVMGD ED 15 L/min 16.1 (0.8) 57 (9) 15.7 (0.7)  78 (11) 14.6 (1.1) 90 (4)20 L/min 12.0 (0.6) 66 (9) 10.4 (0.6) 81.(7) 10.2 (0.4) 89 (8) 25 L/min10.4 (0.6)  75 (11)  8.1 (0.3) 94 (4)  8.2 (0.3) 97 (1)

TABLE 4 Chamber I Volume 0.25 L 0.5 L 0.75 L Flow Rate VMGD ED VMGD EDVMGD ED 15 L/min 18.2 (0.7) 49 (8) 19.3 (1.3) 69 (12) 18.2 (1.9)  79(12) 20 L/min 13.4 (0.5)  43 (13) 12.7 (1.0) 71 (10) 12.5 (0.6) 83 (9)25 L/min 12.0 (0.4) 65 (8) 10.0 (0.4) 85 (7)   9.7 (0.3) 87 (9)

In Tables 2-4, the italicized print indicates peak inspiratory flowrates and inhalation volumes at which the chambers achieved both thegoal of an emitted dose of at least 85% and a dispersion of a VMGD of11.8 μm or less. As is apparent from Tables 2-4, these goals wereachieved for peak inspiratory flow rates of 25 L/min or less and forinhalation volumes of 0.75 L or less. Moreover, the standard deviationswere quite small for the emitted dose (on the order of approximately 10%or less) and for the VMGD (on the order of approximately 1.0 or less).

In addition, statistical analysis was used to extrapolate the resultsfrom these three chambers into ranges of variables that wouldconsistently yield the desired emitted dose and volume mean geometricdiameter. For example optimized combinations of chamber diameter, ventarea, and mouthpiece hole area were determined. It should be apparent toone of ordinary skill in the art that optimization analysis could beperformed for other variable combinations, and for other capsule sizesand powders, in order to optimize the design of the chambers.

Having done a thorough analysis, it has been determined that the presentinvention encompasses an optimized chamber, for a size 00 capsule, thathas:

at least one aperture has an aggregate area of 0.018 to 0.022 squareinches; or

a ring inner diameter of 0.380 to 0.400 inches; or

a chamber inner diameter of 0.400 to 0.440 inches; or

three to five vents; or

a vent width of 0.020 to 0.025 inches; or

a vent length of 0.195 to 0.236 inches; or

a total vent area of 0.014 to 0.024 square inches,

and that when used with a dose of approximately 20 mg of the standardtest powder described above and operated at a peak inspiratory flow rateof 25 L/min or less and an inhalation volume of 0.75 L or less, theemitted dose of powder will be at least 85%, and the VMGD will be about11.8 μm or less.

While the preferred embodiment described above relates to optimizing thedesign of a chamber to have a resistance of at most 0.28 (cmH₂O)^(1/2)/L/min and to provide an emitted dose of at least 85% when thedose of standard test powder is about 20 mg and when the device isoperated at a peak inspiratory flow rate of 25 L/min or less and at aninhalation volume of 0.75 L or less it should be understood that theinvention also encompasses optimizing the chamber to have any othercombination of resistance and emitted dose, at any other combination ofpowder type, dose weight, peak inspiratory flow rate, and inhalationvolume.

Turning now to FIGS. 7A through 7D, a preferred embodiment of a staplesuitable for use in the present invention is shown. The staplepreferably comprises a rectangular length of material that has fourplanar side surfaces 730. Each planar side surface intersects with twoother planar side surfaces to create a total of four non-planar edges736. The staple is preferably bent into a substantially U-shapedconfiguration, thereby having a rounded portion and two prongs 732. Theprongs 732 terminate at two end surfaces 731. As best seen in FIGS. 7A,7C and 7D, end surfaces 731 are diamond-shaped.

The diamond-shaped end surfaces are created by bending the materialabout a non-planar edge. This configuration is best shown in FIGS. 7Band 7D. As can be seen, each prong 732 has an inner surface 738 thatcomprises one of the non-planar edges and an outer surface 740 thatcomprises the opposite non-planar edge. The inner surface 738 of eachprong 732 terminates at the uppermost portion 737 of the diamond-shapedend surface, thereby creating a cutting edge for the prong. The outersurface 740 of the prong 732 terminates at the lowermost portion 735 ofthe diamond-shaped end surface.

Another embodiment of a staple suitable for use in the present inventioncomprises a rectangular length of material that has four planar sidesurfaces. Each planar side surface intersects with two other planar sidesurfaces to create a total of four non-planar edges. The staple ispreferably bent into a substantially U-shaped configuration, therebyhaving a rounded portion and two prongs.

The holes formed by this staple have the appearance of being cut with asharp edge. In addition, the material removed to create the hole ispeeled back and remains well attached to the capsule; thereby preventingthe capsule material from being inhaled by the user when the medicamentis being dispensed.

In addition to improved puncturing performance, drug delivery fromcapsules punctured with the staple depicted in FIGS. 7A-7D is greatlyimproved. The Emitted Dose (ED) and Fine Particle Fraction (FPF) of atest powder was measured at both 20 and 60 Liters per minute (LPM). Inall cases, the aerosol emitted from capsules punctured with the diamondsection staple of FIGS. 7A-7D was improved over a conventional circularstock staple. Most significantly, the FPF of powder delivered at 20liters per minute was improved almost to the level of the FPF at 60liters per minute.

The present invention also relates to a method for dispensingmedicaments to a user through the various embodiments of the disclosedinhalation device. In such a method, a receptacle containing themedicament, e.g., a capsule 219, is placed or formed into cylindricalchamber 210. When the user compresses the inhalation device, staple 230is moved toward capsule 219 thereby puncturing capsule 219 to cause therelease of particles masses into chamber 210. After release into thechamber, the powder is then inhaled by the user through apertures 224and inhalation piece 226. As noted, inhalation piece 226, can beconfigured as either a mouth piece or a nose piece.

For subsequent uses, the user merely replaces emptied capsule 219 withanother capsule 219 that contains a new supply of medicament.Alternatively, medicament is injected into a permanent receptacle thatis formed into chamber 210.

EXEMPLIFICATION Example 1

Particles containing epinephrine made in accordance with the methoddescribed in U.S. Application No. 60/425,349, which is incorporatedherein by reference, were used.

Example 2

Applicant employed two methods to obtain a measure of the emitted dose.A gravimetric analysis and a chemical analysis. This example is astandard operating procedure (SOP) describing the method for obtainingthe emitted dose using gravimetric analysis. This procedure relates tothe release and stability testing of Applicant's products.

Unless otherwise indicated the following equipment, supplies, reagentsand materials were used for both the Gravimetric analysis and thechemical analysis.

-   -   47 mm filter holder (e.g. BGI, Inc., Waltham, Mass.)    -   Filter holder stand    -   Flow meter (e.g. Model 32915-70 or equivalent, Cole-Parmer,        Vernon Hills, Ill.)    -   Flow controller (e.g. Model TPK, Erweka USA, Inc, Milford,        Conn.)    -   Vacuum pump (e.g. Model 1023-101Q-G608X, Gast MFG. CORP., Benton        Harbor, Mich.)    -   Silicon Vacuum tubing with inner diameter (ID) equal to 8±0.5        mm, outer diameter (OD) equal to 14±0.5 mm, and length equal to        50±10 cm (e.g. Peroxide-Cured Silicon tubing, Cole-Parmer,        Vernon Hills, Ill.)    -   Brass tubing connector with ID≧8 mm (e.g. Barbed fitting,        Cole-Parmer, Vernon Hills, Ill.)        Additionally for the Gravimetric analysis, Applicant also used:    -   47 mm glass-fiber filters (A/E 47 mm (Pall Gelman No. 61631))    -   Microbalance (capable of weighing 0.001 mg)    -   Solvents include 100% methanol; 70/30% v/v ethanol/water; 70/30%        v/v ethanol/0.1 M ammonium bicarbonate.

Under controlled environmental conditions of a room temperature ofgreater than about 18° C. but less than about 25° C. and a relativehumidity of between about 20 and about 40%, Applicant prepared theapparatus. Using the solvents listed above, Applicant rinsed theindividual components of the filter holder with the cleaning solvent andthen with methanol and allowed them to dry. Applicant ensured that thefilter holder was completely dry before beginning the analysis. Thefilter was then weighed on a microbalance and its mass was recorded tothe nearest μg. The filter was placed in the filter holder with therough side facing up. After attaching a flow meter to the inlet of thefilter holder, Applicant adjusted the air flow rate using the needlevalve on the flow controller. The flow rate selected was either 60 (±2)L/min for a duration of 2 seconds or a flow rate of 30 (±2) L/min for aduration of 4 seconds. In order to ensure that an airtight seal wasattained, Applicant maintained an equal flow rate in both flow meters(±2 L/min). When an equal air flow rate was not obtained in both flowmeters, Applicant (a) inspected the connections between apparatuscomponents (b) disassembled the apparatus and (c) inspected theintegrity of the connections. Placing an empty capsule into the inhaler,Applicant then attached the inhaler to the filter holder inlet, ensuringan airtight seal was obtained. The air flow rate was adjusted asmentioned above using the needle valve on the flow controller. The airflow rate was recorded to two significant figures. The empty capsule wasthen removed from the inhaler.

After the apparatus was prepared, Applicant then prepared the inhaler.For each run to measure the emitted dose, a new inhaler was used. Afilled capsule was placed in the inhaler. Holding the inhaler verticallywith the mouthpiece up, the capsule was punctured. The inhaler wasplaced in the inlet, ensuring an airtight seal. Next the pump wasactivated using the flow controller for a duration as defined above.

After the activation, Applicant cleaned the inhaler and unit dosesampling apparatus. The inhaler was carefully disassembled and thecapsule was discarded into the appropriate waste container. Theindividual components were rinsed with methanol into a solventcollection container. Thereafter the filter holder was carefullydissembled. Using a microbalance, the powder-laden filter was weighedand its mass recorded to the nearest μg. The filter was discarded intothe appropriate waste container. The individual components of the unitdose sampling apparatus were rinsed with cleaning solvent and then withmethanol into a solvent collection container and allowed to dry. Usingthe following formulae, Applicant calculated the emitted dose.

${ED} = {\frac{\left( {m_{f\; 1} - m_{f\; 0}} \right)}{m_{fw}} \times 100}$

Where ED [%] is the emitted dose of the particle and m_(f0) [mg] is themass of the filter, m_(f1) [mg] is the mass of the powder-laden filterand m_(fw) [mg] is the actual or nominal fill weight.

Applicant reported the emitted dose results (ED) as a percent based onthe actual or nominal fill weight to three significant figures (xx.x %).

Example 3

Another procedure followed for obtaining the emitted dose was a chemicalanalysis. As with the Example above, the following was used:

-   -   47 mm filter holder (e.g. BGI, Inc., Waltham, Mass.)    -   Filter holder stand    -   Flow meter (e.g. Model 32915-70 or equivalent, Cole-Parmer,        Vernon Hills, Ill.)    -   Flow controller (e.g. Model TPK, Erweka USA, Inc, Milford,        Conn.)    -   Vacuum pump (e.g. Model 1023-101Q-G608X, Gast MFG. CORP., Benton        arbor, MI)    -   Silicon Vacuum tubing with inner diameter (ID) equal to 8±0.5        mm, outer diameter (OD) equal to 14±0.5 mm, and length equal to        50±10 cm (e.g. Peroxide-Cured Silicon tubing, Cole-Parmer,        Vernon Hills, Ill.)    -   Brass tubing connector with ID≧8 mm (e.g. Barbed fitting,        Cole-Parmer, Vernon Hills, Ill.).        However for the chemical analysis, the following cleaning        solvents, dissolving solvents and filters were used on the        various parts of the apparatus.

Cleaning solvent Dissolving solvent Filter 100% methanol 100% HPLC gradeA/E 47 mm (Pall methanol Gelman No. 61631) 70/30% v/v ethanol/water 100%HPLC grade A/E 47 mm (Pall methanol Gelman No. 61631) 70/30% v/vethanol/0.1M 25 mM potassium MFMB 47 mm, 1.2 ammonium bicarbonatephosphate 0.1% μm (Whatman) tween 80 pH 7.0 70/30% v/v ethanol/0.1M0.01N HCl 47 mm, 1.2 μm ammonium bicarbonate (Corning) 70/30% v/vethanol/water 92% methanol; 8% A/E 47 mm (Pall 0.01N HCl Gelman No.61631) 70/30% v/v ethanol/0.1M 70/30% v/v 0.05 A/E 47 mm (Pall ammoniumbicarbonate HCl:MeOH Gelman No. 61631)Other equipment included standard volumetric flasks, transfer pipettes,latex or butyl gloves (nitrile gloves should not be used).

As with Example 2 above, for pre- and post-analysis the environment wascontrolled. Under conditions of a room temperature of greater than about18° C. but less than about 25° C. and a relative humidity of betweenabout 20% and about 40%, Applicant prepared the apparatus. Using thesolvents listed above, Applicant rinsed the individual components of thefilter holder with the cleaning solvent and then with methanol andallowed them to dry. Applicant ensured that the filter holder wascompletely dry before beginning the analysis. In certain instances theapparatus was rinsed with water before rinsing with methanol. The filterwas placed in the filter holder with the rough side facing up. Theequipment was assembled. After attaching a flow meter to the inlet ofthe filter holder, Applicant adjusted the air flow rate using the needlevalve on the flow controller. The flow rate selected was either 60 (±2)L/min for a duration of 2 seconds or a flow rate of 30 (±2) L/min for aduration of 4 seconds. In order to ensure that an airtight seal wasattained, Applicant maintained an equal flow rate in both flow meters(±2 L/min). When an equal air flow rate was not obtained in both flowmeters, Applicant (a) inspected the connections between apparatuscomponents (b) disassembled the apparatus and (c) inspected theintegrity of the connections. Placing an empty capsule into the inhaler,Applicant then attached the inhaler to the filter holder inlet, ensuringan airtight seal was obtained. The air flow rate was adjusted asmentioned above using the needle valve on the flow controller. The airflow rate was recorded to two significant figures. The empty capsule wasthen removed from the inhaler.

After the apparatus was prepared, Applicant then prepared the inhaler.For each run to measure the emitted dose, a new inhaler was used. Afilled capsule was placed in the inhaler. Holding the inhaler verticallywith the mouthpiece up, Applicant punctured the capsule. The inhaler wasplaced in the inlet, ensuring an airtight seal. Next the pump wasactivated using the flow controller for a duration as defined above.

After the activation, Applicant cleaned the inhaler and unit dosesampling apparatus. The inhaler was carefully disassembled and thecapsule was not discarded as in the Example above. Instead the capsulewas inspected and observations were recorded. The individual inhalercomponents were rinsed including the capsule, with the sample solventinto a volumetric flask. It should be noted that the Applicant tappedand removed all particle from the capsule using a round-ended microspatula then rinsed the spatula with the sample solvent into thevolumetric flask. However, they did not add the capsule to thevolumetric flask. The filter holder was disassembled and the individualcomponents of the filter holder were rinsed, including the filter, withthe sample solvent into a volumetric flask. In some instances, theApplicant placed the filter in the volumetric flask. Sample solutionswere transferred to suitable containers, e.g., scintillation vials, forstorage and chemical analysis. The filter holder components were rinsedwith cleaning solvent and then with methanol into a solvent wastecontainer and allowed to dry. In some instances, Applicant, first rinsedall components with cleaning solvent, followed by further rinsing withwater and then methanol.

The calculations were performed as above.

Example 4

Applicant conducted experiments in humans to evaluate the in vivo dosedelivery characteristics of the delivery system of the instant inventionover a wide range of inspiratory flow rates. The in vivo dose deliveryof the pulmonary delivery system of the instant invention wascharacterized at a target peak inspiratory flow rate (PIFR) of 60 L/min(Dunbar et al., Int. J. Pharm., 245, 2002).

Twelve healthy volunteers participated in a single center, randomized,three period, cross-over study. Each volunteer performed the followingthree inhalation maneuvers: (i) a targeted peak inspiratory flow rate(PIFR) of 20 L/min, (ii) a deep comfortable inhalation, and (iii) a deepforced inhalation. Volunteers inhaled the radiolabeled placebo powdersitting upright, with their head and lungs posterial to the planar gammacamera. After a 5 s breath hold, the volunteers were instructed toexhale into a filter. Peak inspiratory flow rate (PIFR) and inhaledvolume (V) were obtained during the inhalation of the dose using aspirometer (Koko Spirometer, Pulmonary Data Services Inc., Louisville,Colo.). Immediately following the radiolabeled dose, posteriorscintigraphic images were taken using a planar gamma camera (DIACAM,Siemens Gammsonics, Inc., Hoffman Estates, Ill.). Four regions ofinterest were drawn around the left lung, right lung, stomach, andoropharynx (which included the upper part of the trachea). Aftersubtracting the background activity, each region was corrected fortissue attenuation. The radioactivity in the pre-dosed capsule and theradioactivity remaining in the inhaler mouthpiece, inhaler body,post-dosed capsule, and exhalation filter were measured by scintigraphyusing a high sensitivity NaI detector (Model 905, Perkin-Elmer, OakRidge, Tenn.). PIFR, emitted dose (ED), and lung deposition of the totaldose were the response factors evaluated in this study.

Scintigraphy images from a single subject were taken. The mean ED andlung deposition across all three inhalation maneuvers were 87 (4) % and51 (10) %, respectively (sd in parentheses). The range of PIFRs obtainedin this study was 12-86 L/min. The ED and the lung deposition of thetotal dose as a function of PIFR or as a function of inhaled volume areshown in FIGS. 12 and 13 or 19 and 20, respectively.

Using 5 mg placebo, the powder was delivered via a simple, capsulebased, passive dry powder inhaler such as the preferred inhalerdescribed herein. The powder was radiolabeled with 99 mTc using afluidized bed process (Dunbar et al., Int. J. Pharm., 245, 2002).Validation experiments were conducted to ensure the radiolabelingprocess did not significantly affect the aerodynamic particle sizedistribution (aPSD) of the emitted dose and the radioactive aPSD matchedthe mass aPSD. The mass aPSD of the unlabeled powder, the mass aPSD ofthe labeled powder, and the radioactive aPSD of the labeled powder wereobtained using an 8-stage Andersen cascade impactor (AndersenInstruments, Smyrna, Ga.) with a USP induction port, shown in FIG. 11.

Applicant observed that the in vivo dose delivery was characterized byhigh emitted doses and high lung deposition, with low variability. Lungdeposition was independent of PIFR by analysis of variance across thewide range of inspiratory flow rates (p=0.498).

While various embodiments of the present invention have been describedabove, it should be understood that they have been presented by way ofexample only, and not limitation. For example, the present invention isnot limited to the physical arrangements or dimensions illustrated ordescribed. Nor is the present invention limited to any particular designor materials of construction. As such, the breadth and scope of thepresent invention should not be limited to any of the above-describedexemplary embodiments, but should be defined only in accordance with thefollowing claims and their equivalents.

1. A method of delivering an agent to the pulmonary system of acompromised patient, in a single breath-activated step, comprisingadministering a particle mass comprising an agent from an inhalercontaining less than 5 milligrams of the mass, wherein at least about50% of the mass in the receptacle is delivered to the pulmonary systemof the patient.
 2. A method of claim 1, wherein the compromised patienthas a peak inspiratory flow rate of about 15 liters per minute.
 3. Amethod of claim 1, wherein the inhaler contains less than 4 milligramsof the mass.
 4. A method of claim 1, wherein the mass has a tap densityof less than about 0.4 g/cm³.
 5. A method of claim 1, wherein the massmean geometric diameter of the mass emitted from the inhaler is betweenabout 3 microns and 15 microns.
 6. A method of claim 1, wherein the massmean geometric diameter of the mass emitted form the inhaler is betweenabout 3 microns and 10 microns.
 7. A method of claim 1, wherein the massmean aerodynamic diameter of the mass emitted from the inhaler isbetween about 1 and 5 microns.
 8. A method of claim 1, wherein the massmean aerodynamic diameter of the mass emitted from the inhaler isbetween about 1 and 3 microns.
 9. A method of claim 1, wherein theemitted dose from the inhaler is greater than about 70%.
 10. A method ofclaim 1, wherein the mass consists essentially of spray-dried particles.11. A method of claim 1, wherein the inhaler comprises: a first casingportion; a cylindrical chamber, defined by a wall of circularcross-section, coupled to the first casing portion, the chamber having aproximal end and a distal end, the chamber comprising a ringcircumferentially coupled to an inner surface of the chamber; and asecond casing portion removably coupled to the first casing portion, thesecond casing portion comprising an inhalation portion disposed at theproximal end of the chamber when the first and the second casingportions are coupled, the inhalation portion comprising a hemisphericregion defining a plurality of apertures configured to emit the mass.12. A method of claim 11, wherein the ring is disposed at approximatelya midpoint of the chamber.
 13. A method of claim 11, wherein saidinhaler further comprises a plurality of slits defined by said wall,said plurality of slits configured for introducing air into saidchamber.
 14. A method of claim 11, wherein the inhaler further comprisesa movable puncturing tool, disposed in said first casing portion, forpuncturing a receptacle containing the mass.
 15. A method of claim 1,wherein the inhaler possesses a resistance of less than about 0.28 (cmH₂O)^(1/2)/L/min.
 16. A method of claim 15, wherein the inhalationvolume of the patient is less than 1.0 L or less.
 17. A method of claim11, wherein the receptacle has a volume of less than about 0.67 cm³. 18.A method of claim 11, wherein the receptacle has a volume of less thanabout 0.48 cm³.
 19. A receptacle containing less than 5 milligrams ofparticle mass comprising an agent wherein, upon delivery to thepulmonary system of a comprised patient, in a single breath-activatedstep, at least about 50% if the mass in the receptacle is delivered tothe pulmonary system of the patient.
 20. An inhaler for use in a methodfor delivering an agent to the pulmonary system of a compromisedpatient, in a single breath-activated step, comprising administering aparticle mass comprising an agent from an inhaler containing less than 5milligrams of the mass, wherein at least about 50% of the mass in thereceptacle is delivered to the pulmonary system of the patient.